Overview of Lung Transplantation Changing the practice of clinical lung transplantation Ex vivo lung perfusion, personalized medicine for the organ, engineering "super organs"

1. Lung Transplantation:
Where we are and Where we are going…
Shaf Keshavjee MD MSc FRCSC FACS
Director, Toronto Lung Transplant Program
Surgeon-in-Chief, University Health Network
James Wallace McCutcheon Chair in Surgery
Professor, Division of Thoracic Surgery and Institute of
Biomaterials and Biomedical Engineering
University of Toronto

2. Disclosure
• Vitrolife – Research support and clinical trial
• Astellas Canada – Research Grant
• CIHR/ Wyeth (Pfizer) – Chair in
Transplantation Research
• Axela, Xceed Molecular – Research Grant
• Will discuss off label use of devices
2

3. OVERVIEW
Lung Transplantation
 Overview of Lung Transplantation:
 Activity, indications outcomes
 Changing the practice of clinical lung transplantation
 Expansion of indications
 Bridge to transplant
 New Horizons
 Ex vivo lung perfusion, personalized medicine for the
organ, engineering “super organs”

4. Indications for Lung Transplantation
Adult (1983-Apr 2012)
Adults ILD / IPF
BAC
PAH
CF
Eisenmenger's
COPD /Emphysema
ReTx
Other
N=1245 (96.3 %)

5. Indications for Transplantation
Pediatric (1983-Apr 2012)
N=48 (3.7 %)

6. 6
No of Tx / yr
100
120
0
20
40
60
80
83
84
85
BLT
SLT
HLT
86
87
88
89
90
91
92
93
94
95
96
97
Year
98
99
'00
'01
'02
'03
'04
1983-Apr 2012 (YTD)
'05
'06
'07
'08
'09
'10
Number of Transplants / Year
'11
'12

7. 7
No of Tx / yr
20
40
60
80
100
120
0
'83
'84
'85
'86
Adults
'87
'88
'89
'90
'91
Peds
'92
'93
'94
'95
'96
'97
Year
'98
'99
N Peds =48
'00
'01
'02
(1983-Apr 2012)-YTD
'03
Adult vs. Pediatric
'04
'05
Total Transplants / Year
'06
'07
'08
'09
'10
'11
'12

8. NUMBER OF LUNG TRANSPLANTS REPORTED
BY YEAR AND PROCEDURE TYPE
www.ishlt.org
3500 3272
2972
Bilateral/Double Lung 2917
3000 2791
Single Lung
Number of transplants
2567
2500
2216
n = 38,119 1971 2008
2000 1783
1699
1509 1548 1559
1411 1389
1500 1291
1160
972
1000
758
449
500
204
38 89
5 7
0
19 5
19 6
19 7
19 8
19 9
19 0
19 1
19 2
19 3
19 4
19 5
19 6
19 7
19 8
20 9
20 0
20 1
20 2
20 3
20 4
20 5
20 6
20 7
20 8
09
8
8
8
8
8
9
9
9
9
9
9
9
9
9
9
0
0
0
0
0
0
0
0
0
19
ISHLT 2011
J Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132

9. LUNG TRANSPLANTS:
Recipient and Donor Age by Year of Transplant
100% 50
Median donor age (years)
80% 40
% of transplants
60% 30
40% 20
20% 10
0% 0
87
88
89
90
91
92
93
94
95
96
97
98
99
00
01
02
03
04
05
06
07
08
09
10
19
19
19
19
19
19
19
19
19
19
19
19
19
20
20
20
20
20
20
20
20
20
20
20
Year of Transplant
0-11 12-17 18-34 35-49 50-59 60+ Median Donor Age
ISHLT 2011
J Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132

10. AVERAGE CENTER VOLUME
Lung Transplants
60 24
50 20
Percentage of transplants
Number of centers
40 16
30 12
54
20 39 8
10 28 23 4
16
7 7
0 0
1-4 5-9 10-19 20-29 30-39 40-49 50+
Average number of lung transplants per year
Number of centers Percentage of transplants
ISHLT 2011
J Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132

11. ADULT LUNG TRANSPLANTS (1/1997-6/2009)
Risk Factors for 1 Year Mortality
Center Volume
2
Relative Risk of 1 Year Mortality
1.5
1
0.5
p < 0.0001
0
5 10 15 20 25 30 35 40 45 50
Center Volume (cases per year)
ISHLT 2011
J Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132

12. ADULT LUNG TRANSPLANTATION
Kaplan-Meier Survival by Era (Transplants: January 1988 – June 2009)
100 Survival comparisons by era
1988-1994 (N=4,548) 1988-94 vs. 1995-99: p = 0.4858
1995-1999 (N=6,795) 1988-94 vs. 2000-6/09: p <0.0001
2000-6/2009 (N=20,728) 1995-99 vs. 2000-6/09: p <0.0001
80
Survival (%)
60
N at risk =552
40
N at risk = 841
20
1988-1994: 1/2-life = 4.7 Years; Conditional 1/2-life = 7.9 Years N at risk = 702
1995-1999: 1/2-life = 4.8 Years; Conditional 1/2-life = 7.5 Years
2000-6/2009: 1/2-life = 5.9 Years; Conditional 1/2-life = 8.0 Years
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Years
ISHLT 2011
J Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132

13. ADULT LUNG TRANSPLANTATION
Kaplan-Meier Survival by Age Group (Transplants: January 1990 – June 2009)
100
HALF-LIFE 18-34: 6.4 Years; 35-49: 6.7 Years; 50-59: 5.3 Years; 60-65: 4.4 Years; >65: 3.5 Years
80
Survival comparisons
All p-values significant at p < 0.0001 except 18-34 vs. 35-49: p =0.1708
Survival (%)
60
40
18-34 (N = 5,523)
35-49 (N = 7,980)
20
50-59 (N = 11,389)
60-65 (N = 5,685)
>65 (N = 1,217)
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Years
ISHLT 2011
J Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132

14. ADULT LUNG TRANSPLANTATION
Kaplan-Meier Survival By Diagnosis (Transplants: January 1990 – June 2009)
100
Alpha-1 (N=2,349) CF (N=4,828) COPD (N=10,741)
IPF (N=6,478) IPAH (N=1,189) Sarcoidosis (N=756)
80
HALF-LIFE Alpha-1: 6.3 Years; CF: 7.4 Years; COPD: 5.3 Years;
IPF: 4.5 Years; IPAH: 4.9 Years; Sarcoidosis: 5.3 Years
Survival (%)
60
40
Survival comparisons
All comparisons with Alpha-1 and CF are
20 statistically significant at < 0.01
COPD vs. IPF: p < 0.0001
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Years
ISHLT 2011
J Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132

15. Waiting List, Transplants and Donors
(All Organs-Ontario)
(Source: TGLN 1991-2011)
2500
1892 1913 1857
2000 1745
1766 1720
1650 1676 16831631
1557
1461 1498
1408
1500
Number of Patients
1271
1116 1171
926 953 916 940
837 827 928 875 852
1000 799 765
667 700 641 686 693 727
617
536 529 498
528 456 499 507
500
133 145 139 151 150 200 175 218 200 220
161 151 150 133 166 128 137 143 153 148 172
0
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
Waiting List(all) Transplants(all) Ont. Donors©
15

16. Death on Waiting List, Total LTx/yr &
Listed/yr
2004-Jan/2012 (YTD)
Numbers
16

17. Solutions to Deaths on the Wait List
•Keep the patient alive longer and in
better condition  Bridge to
Transplant
•Increase the supply of donor organs
17

18. Selection of ECLS Support Mode /Configuration
Cypel/Keshavjee ECMO Red Book, 4th edition, 2011.

19. NovalungR

20. Novalung
Pumpless A-V Mode: Femoral Artery to Femoral
Vein (extra-corporeal ventilation)

21. V-V ECLS
CardioHelp Device

22. Novalung iLAactivve

23. Dual Lumen Canula (AvalonR)
• One canula inserted through right
internal jugular vein
• Drainage from IVC and SVC 
oxygenated blood returned to
right atrium
• Allows mobilisation of extubated
patients
Garcia/Griffith et al J Thorac Cardiovasc Surg 2010;139:e137-9

25. Bridge to Lung Transplant for PAH Patients
Simple Atrial Septostomy is Unsatisfactory
PA LA
RV failure 20 to Pulmonary Vascular Resistance
Atrial Septostomy:  provides pressure
decompression  problem: R-L
shunt, hypoxia

26. Novalung PA to LA
Bridge to Lung Transplant for PAH Patients
“The Oxygenating Septostomy”
PA LA
1. Pumpless
2. Effectively: an oxygenating shunt  provides pressure
decompression AND gas exchange
Strueber / Keshavjee et al. Am J Transplant 2009; 9: 853-7.

27. June 2008

28. Dec 2008

29. Number of days on PA-LA Novalung
200
Days on PA-LA Novalung
180
160
140
120
100
80 69*
60
40 30*
21
20 9 14
*Pediatric patients
7 6

30. ECLS decreases wait list mortality in
iPAH patients: Toronto experience
Wait list mortality: 22%  0%
25
Number of patients
20
Patients liste
15
Patients tran
10 Died on wait
p=0.03
5
de Perrot 0 al J Heart Lung Transplant 2011
et
1998-2005 2006-2010

31. ECLS Toronto Experience
2000 – 2012 (10Apr2012)
n = 100
20
18 Bridge to recovery (non-Tx)
16 Bridge to recovery post-transplant
14
Nr of ECLS
Bridge to lung transplant
12
10
8
6
4
2
0
2000 2002 2004 2006 2008 2010 2012(ytd)
Year

32. IMPROVING SUPPLY:
Focus on Organ Recovery and Repair Rather than
Simply Focusing on Slowing Down Death…
Good
Better

33. Normothermic Ex Vivo Lung Perfusion
(EVLP)
• Time to accurately assess - diagnose
• Option to treat/repair/recover
• Opportunity to reassess - confirm results of treatment

34. TORONTO EX VIVO LUNG
PERFUSION (EVLP) SYSTEM
Perfusion : 40% CO
Ventilation: 7cc/kg, 7BPM, PEEP 5, FiO2 = 21%
J Heart Lung Transplant 2008; 27(12):1319-25.

35. DEVELOPMENT OF A STABLE AND RELIABLE
EX VIVO LUNG PERFUSION TECHNIQUE
Cypel/Keshavjee. Technique for Prolonged Normothermic Ex Vivo Lung
Perfusion. J Heart Lung Transplant 2008;27(12):1319-25.

36. Normothermic Ex vivo Lung Perfusion in
Clinical Transplantation – HELP Trial

37. HELP II TRIAL
CLINICAL TRANSPLANTATION OF EX VIVO
PERFUSED LUNGS
N=52 transplants to date
Toronto General Hospital OR

38. Bronchoscopy

39. LUNG X-Ray

40. Ex vivo treatment opportunities Donor
lung injuries
• 1- Pulmonary Edema
• 2- Brain death associated inflammation
• 3- Infection, Pneumonia
• 4- Aspiration
• 5- Pulmonary emboli
• 6- Ischemia-reperfusion injury
• 7- Immunologic preparation

41. Diagnose Specific Injuries:
The expression ratio of IL-6/IL-10 in the donor lung predicts
recipient outcome
1.0
0.8 Low risk group
Survival
0.6 Intermediate risk group
High risk group
0.4
0.2 The Wilcoxon test
P value: 0.0004
0.0
0 365 730 1095 1460 1825
Survival Days
Kaneda H / Keshavjee S et al. Pre-implantation multiple cytokine mRNA expression analysis of donor lung
grafts predicts survival after lung transplantation in humans. Am J Transplant 2006 Mar; 6 (3):544-51.

42. Monitoring the
Response to
Pre-EVLP sample 1-22 Post-EVLP sample 1-22
Ex Vivo
Treatment
Ziplex Inflammatory
Tip ChipR (Axela)
Pre EVLP Post EVLP

43. Functional Repair of Human Donor Lungs
by Ex Vivo IL-10 Gene Therapy
Delivery of IL-10 by EVLP Ad Gene Therapy to injured human donor lungs
resulted in improved lung function
PaO2/FiO2 PVR
Change from Baseline
300 * 600
(dynes.sec.cm-5)
400
200
(mmHg)
200
100 0
-200
0
-400
-100 -600 *
EVLP/AdIL-10 EVLP
M Cypel, M Liu, M Rubacha, J C Yeung, S Hirayama, M Anraku, M Sato, J Medin, BL
Davidson, M de Perrot, TK Waddell, A S Slutsky, S Keshavjee. Sci Trans. Med 1:4ra9; 2009.

44. April 14th 2011, vol. 364, no. 15, pp. 1431-1440.
44

45. Resolution of pulmonary edema during
EVLP
1h EVLP
Donor P/F 230
3h EVLP
Recipient P/F 420

46. Donor, EVLP and Recipient P/F (n=35)
P/F
600
500
400
mmHg
300
200
100
0
1h
2h
3h
4h
or
U
IC
on
D
EVLP

47. Overall Survival
100
Control (n=116)
80 EVLP (n=23)
Percent survival
60
p=0.77
40 median f/u 635 days
20
0
0 200 400 600 800 1000
Days after transplantation

48. EVLP Activity /Year
1983-Apr 2012(YTD)
120
EVLP pre Tx
100
LuTx-no EVLP
80
No of Tx / yr
60
40
20
0
83
94
84
85
86
87
88
89
90
91
92
93
95
96
97
98
99
'11
'00
'01
'02
'03
'04
'05
'06
'07
'08
'09
'10
'12
Year
53/65 EVLP was successfully Transplanted
48

49. Operative (30 day) Mortality by year
1983-April 2012 (YTD)
120
100 102 102
Death <=30-d
100 87 85
Number of transplants 84
Number of TX
80 68
64
59
54
60 50
42 40
36 38
32303133
40 2727 2524
14
15 13
20 6 6
1 2 1 3 3 1 2 7 2 1 2 3 1 4 4 2 39 7 4 25 5 4 6 1
0 1 8 321
0
Year
49

50. The Future of Transplantation is here…
The “Organ Repair Center”
Lung Heart
Liver Kidney

51. Case Report (April 2011)
• 52 y old male in US
• Viral Pneumonia
• 7 days ventilator – extubated
• Day 14 – re-intubated
• Day 22 – VV – ECMO
• Day29 – deterioration – bleeding complications
• Day 30 urgently listed for LTx
• Day 32 – Donor is identified in another state.
• Massive pulmonary edema and P/F 230mmHg
Love R et al. Am J Transplantation 2012. In press

53. April 2011

54. Love R et al. Am J Transplantation 2012. In press

55. Ex vivo Lung Perfusion:
The Toronto Experience
• Clinically feasible
• Increases the utilization of donor lungs (20% of our current program activity)
• Equivalent outcomes  trend to improved post transplant lung function
• Demonstrated the concept of the “organ repair center”
• New era of transplantation:
• “Personalized medicine for the organ”:
• More accurate assessment
• Treatment  specific injuries
• Lung transplantation with more predictable outcome

56. The Toronto Lung Transplant Team

58. Webinar Conducted by
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